Submissions for variant NM_002834.5(PTPN11):c.1530G>T (p.Gln510His)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001798	SCV001159456	pathogenic	not specified	2019-02-20	criteria provided, single submitter	clinical testing	The PTPN11 c.1530G>T; p.Gln510His variant (rs397507550) is reported in the literature in two unrelated fetuses with prenatal symptoms of Noonan syndrome, and it was not observed in the parents of either affected fetus, indicating a de novo origin (Gezdirici 2017). Additionally, a variant giving rise to the same amino acid change (c.1530G>C; p.Gln510His) was observed in an individual affected with LEOPARD syndrome (Wakabayashi 2011). The c.1530G>T; p.Gln510His variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamine at codon 510 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Arg, Glu, and Pro) have been reported in individuals with Noonan syndrome or LEOPARD syndrome and are considered pathogenic (Aoki 2008, Carcavilla 2013, Ganigara 2011, Wakabayashi 2011). Based on available information, the p.Gln510His variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. Ganigara M et al. LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation. Ann Pediatr Cardiol. 2011 Jan;4(1):74-6. Gezdirici A et al. How necessary is to analyze PTPN11 gene in fetuses with first trimester cystic hygroma and normal karyotype? J Matern Fetal Neonatal Med. 2017 Apr;30(8):938-941. Wakabayashi Y et al. Implantable cardioverter defibrillator for progressive hypertrophic cardiomyopathy in a patient with LEOPARD syndrome and a novel PTPN11 mutation Gln510His. Am J Med Genet A. 2011 Oct;155A(10):2529-33.
CeGaT Center for Human Genetics Tuebingen	RCV001171895	SCV001334787	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411945	SCV004107520	pathogenic	PTPN11-related condition	2023-05-19	criteria provided, single submitter	clinical testing	The PTPN11 c.1530G>T variant is predicted to result in the amino acid substitution p.Gln510His. This variant has been reported in prenatal cases with cystic hygroma (Gezdirici et al. 2017. PubMed ID: 27193571; Supplemental Table S2, Leach et al. 2018. PubMed ID: 29907801) and hydrops fetalis (Supplemental Table 1, Gabriel et al. 2021. PubMed ID: 34958143). Of note, another variant impacting the p.Gln510 amino acid was also reported in prenatal cases with cystic hygroma [c.1530G>T (p.Gln510His), Supplemental Table S2, Leach et al. 2018. PubMed ID: 29907801]. In addition, another variant impacting the p.Gln510 amino acid was also reported in an individual tested for Noonan syndrome and related conditions [c.1528C>G (p.Gln510Glu), Supplemental Table S3, Leach et al. 2018. PubMed ID: 29907801]. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261024	SCV001438421	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing